The long range objective of this laboratory is the elucidation of the mechanisms of differential regulation of hemoglobin synthesis in human erythroid cells in health an disease. The factors responsible for the control of production of the structurally different hemoglobin types are not well-understood nor are the mechanisms of defective synthesis in certain thalassemia syndromes. We are particularly interested at this time in gaining understanding of the control mechanisms regulating relative synthesis of fetal (HbF) and adult (HbA) hemoglobin and the mechanism responsible for deficient Alpha globin synthesis in an non-deletional form of Alpha-thalassemia. Understanding the control mechanisms may lead to the ability to manipulate the amounts of adult and fetal hemoglobin in patients. Such an ability to manipulate hemoglobin levels would be of great therapeutic importance in such hematological disorders as sickle cell anemia, thalassemia and aplastic anemia. We are using a model in vitro system involving culture of erythroid precursors derived from fetal liver and umbilical cord blood and are studying hemoglobin synthesis in these cultures, hoping to find a means of altering the relative synthesis of HbA and HbF. We are also studying globin gene structure in a non-deletional form of Alpha-thalassemia utilizing restriction endonuclease techniques. We plan to apply recombinant DNA techniques to analyse this disorder. We hope to apply these techniques to the study of globin gene structure in adult and getal cells with the aim of detecting some structural change in the genes for Gamma and Beta tissues. We also plan to study the ability of erythrocytes to rid themselves of excess globin chains. Excess unpaired globin chains are damaging to the red cell and proteolytic systems active in their removal may be important in lessening morbidity of certain thalassemia syndromes.